Basic Research
Copyright ©2006 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Aug 28, 2006; 12(32): 5160-5167
Published online Aug 28, 2006. doi: 10.3748/wjg.v12.i32.5160
Signaling pathways involved in the inhibition of epidermal growth factor receptor by erlotinib in hepatocellular cancer
Alexander Huether, Michael Höpfner, Andreas P Sutter, Viola Baradari, Detlef Schuppan, Hans Scherübl
Alexander Huether, Michael Höpfner, Andreas P Sutter, Viola Baradari, Hans Scherübl, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Medical Clinic I, Gastroenterology/Infectious Diseases/Rheumatology, Berlin, Germany
Detlef Schuppan, Harvard Medical School, Beth Israel Deaconess Medical Center, Division of Gastroenterology and Hepatology, Boston, United States
Author contributions: All authors contributed equally to the work.
Supported by Deutsche Forschungsgemeinschaft (DFG), Deutsche Krebshilfe and Sonnenfeld-Stiftung Berlin
Correspondence to: Professor, Dr. Hans Scherübl, Charité- Universitätsmedizin Berlin, Campus Benjamin Franklin, Medical Clinic I, Hindenburgdamm 30, 12200 Berlin, Germany. hans.scherü
Telephone: +49-30-84453534 Fax: +49-30-84454481
Received: December 3, 2005
Revised: January 8, 2006
Accepted: January 14, 2006
Published online: August 28, 2006

AIM: To examine the underlying mechanisms of erlotinib-induced growth inhibition in hepatocellular carcinoma (HCC).

METHODS: Erlotinib-induced alterations in gene expression were evaluated using cDNA array technology; changes in protein expression and/or protein activation due to erlotinib treatment as well as IGF-1-induced EGFR transactivation were investigated using Western blotting.

RESULTS: Erlotinib treatment inhibited the mitogen activated protein (MAP)-kinase pathway and signal transducer of activation and transcription (STAT)-mediated signaling which led to an altered expression of apoptosis and cell cycle regulating genes as demonstrated by cDNA array technology. Overexpression of proapoptotic factors like caspases and gadds associated with a down-regulation of antiapoptotic factors like Bcl-2, Bcl-XL or jun D accounted for erlotinib's potency to induce apoptosis. Downregulation of cell cycle regulators promoting the G1/S-transition and overexpression of cyclin-dependent kinase inhibitors and gadds contributed to the induction of a G1/G0-arrest in response to erlotinib. Furthermore, we displayed the transactivation of EGFR-mediated signaling by the IGF-1-receptor and showed erlotinib’s inhibitory effects on the receptor-receptor cross talk.

CONCLUSION: Our study sheds light on the under-standing of the mechanisms of action of EGFR-TK-inhibition in HCC-cells and thus might facilitate the design of combination therapies that act additively or synergistically. Moreover, our data on the pathways responding to erlotinib treatment could be helpful in predicting the responsiveness of tumors to EGFR-TKIs in the future.

Keywords: Epidermal growth factor receptor, Insulin-like growth factor receptor, TarcevaTM, Signal transducer of activation and transcription, Extracellular regulated kinase, Gene expression